Neuroscience
-
The primary sensory cortex exhibits neuroplastic changes responding to sensory disturbances, and GABAergic synaptic transmission plays a critical role in the regulation of plasticity. The insular cortex (IC) integrates orofacial nociceptive signals conveyed via myelinated Aδ- and unmyelinated C-fibers. However, it has been unknown whether a disturbance of nociceptive inputs, such as a deletion of the peripheral nerves, alters GABAergic local circuit in IC. ⋯ These results suggest that capsaicin treatment depresses IPSCs via a postsynaptic mechanism. To confirm this possibility, the variance-mean analysis of unitary IPSCs was employed and we found that quantal size of GABAergic synaptic transmission was smaller in capsaicin-treated rats than in sham-treated rats. These results suggest that ablation of C-fibers induces plastic changes in GABAergic synaptic transmission by decreasing postsynaptic GABAA receptor-mediated conductance, which is a possible mechanism of the facilitative excitation in IC of capsaicin-treated rats.
-
Children and adolescents have the highest rates of traumatic brain injury (TBI), with mild TBI (mTBI) accounting for most of these injuries. Adolescents are particularly vulnerable and often suffer from post-injury symptomologies that may persist for months. We hypothesized that the combination of resveratrol (RES), prebiotic fiber (PBF), and omega-3 fatty acids (docosahexaenoic acid (DHA)) would be an effective therapeutic supplement for the mitigation of mTBI outcomes in the developing brain. ⋯ A behavioral test battery designed to examine symptomologies commonly associated with mTBI was administered. Following the test battery, tissue was collected from the prefrontal cortex (PFC) and primary auditory cortex for Golgi-Cox analysis of spine density, and for changes in expression of 6 genes (Aqp4, Gfap, Igf1, Nfl, Sirt1, and Tau). 3S treatment altered the behavioral performance of sham animals indicating that dietary manipulations modify premorbid characteristics. 3S treatment prevented injury-related deficits in the longer-term behavior measures, medial prefrontal cortex (mPFC) spine density, and levels of Aqp4, Gfap, Igf1, Nfl, and Sirt1 expression in the PFC. Although not fully protective, treatment with the supplement significantly improved post-mTBI function and warrants further investigation.
-
Previous studies have shown that leptin resistance is a key feature that leads to gestational metabolic adaptions. We hypothesized that leptin sensitivity in the ventromedial nucleus of the hypothalamus (VMH) plays a critical role regulating gestational metabolic changes. In the present study, we generated a mouse model carrying ablation of the suppressor of cytokine signaling 3 (SOCS3) in steroidogenic factor-1 (SF1) cells, which include the VMH, in order to investigate whether increased leptin sensitivity in this neuronal population prevents at least part of the metabolic changes typically observed during gestation and lactation. ⋯ Unexpectedly, SF1 SOCS3 KO mice exhibited glucose intolerance during pregnancy. SF1 SOCS3 KO mice also presented a lower body weight (-3%; p < 0.05) during mid and late lactation, although food intake, litter size and offspring growth were not affected. Our findings suggest that increased leptin sensitivity in the VMH causes modest metabolic effects and is not sufficient to prevent major metabolic adaptations of pregnancy and lactation.
-
Mutant SOD1 causes amyotrophic lateral sclerosis (ALS) by a dominant gain of toxicity. Previous studies have demonstrated therapeutic potential of mutant SOD1-RNAi delivered by intrathecal (IT) injection of recombinant adeno-associated virus (rAAV). However, optimization of delivery is needed to overcome the high degree of variation in the transduction efficiency and therapeutic efficacy. ⋯ To test how these effects influence the outcome of RNAi therapy, we used slow and fast IT injection to deliver rAAVrh10-GFP-amiR-SOD1, a rAAV vector that expresses GFP and an artificial miRNA targeting SOD1, in SOD1-G93A mice. Both slow and fast IT injection produced therapeutic efficacy but the slow injection trended slightly toward a better outcome than the fast injection. These results demonstrate that IT injection speed influences the predominance of gene delivery at different CNS sites and should be taken into consideration in future therapeutic trials involving IT injection.